U.S. Pat. No. 4,654,628 describes alkyl aminotetraline derivatives exhibiting dopaminergic activity. Among these compounds, rac-(I) is found,

Subsequent studies, whose results are described in U.S. Pat. No. 4,657,925, show that the dopaminergic action of enantiomer (6S)-(−)-5,6,7,8-tetrahydro-6-[propyl-(2-thienyl)ethyl]amino-1-naphthol, hereinafter referred to as (I), is up to 140 times higher than that of its enantiomer (6R)-(+)-5,6,7,8-tetrahydro-6-[propyl-(2-thienyl)ethyl]amino-1-naphthol.
U.S. Pat. No. 4,885,308 describes the use of (I), active ingredient known as Rotigotine, for the treatment of Parkinson's disease.
There is, therefore, a need for a process to prepare this active ingredient.
In the processes described so far—U.S. Pat. No. 4,654,628 and U.S. Pat. No. 4,657,925—for the preparation of rac-(I), the last synthesis step relies on the deprotection of a phenol group by hydrolysis of the corresponding methyl ether. This hydrolysis requires drastic acid conditions, e.g., 48% HBr at high temperature (J. Med. Chem., 1979, v. 22, n. 12, 1469-1475) or BBr3 at low temperature (Pharmaceutisch Weekblad Scientific Edition, 1985, 7, 208-211). Due to the fact that the thienyl group is not very stable against these acid conditions, a large number of impurities are formed in this final synthesis step.
U.S. Pat. No. 6,372,920B1 discloses the preparation of (I) by alkylation of (−)-5-hydroxy-N-n-propyl-2-aminotetraline (V) with a large excess of 2-(2-thienyl)ethanol 4-toluenesulfonate in xylene at reflux for 32 hours in the presence of sodium carbonate at 0.6 molar ratio in relation to the starting aminotetraline. According to the authors, the use of alkali metal carbonates or bicarbonates with a molar ratio value lower than 1.9 in relation to the starting aminotetraline reduces the formation of byproducts. However, according to our own experience, in the O-alkylation of phenol, a considerable number of compounds are formed as byproducts.
In accordance with the above, none of the preparation methods for (I) described so far seems to be satisfactory for its industrial application. There is, therefore, a need to provide an alternative industrial process for the preparation of rotigotine (I).